Traditional synthetic organic chemistry has been developed with the development of target oriented synthesis. Many organic chemists have been engaged in the investigation and development of new reactions in the synthesis of various natural products. In the target oriented synthesis, a specific natural product is targeted, and then synthesized. Thus, the obtained compound can be represented by one point as the distribution in chemical space. Therefore, it can be said that target oriented synthesis is very limited in terms of the diversity of compound.
Accordingly, many efforts have been made to improve specific chemical properties of the compound and track down the more biologically active compound, which results in the development of combinatorial chemical synthesis.
Combinatorial chemical synthesis is a new synthetic method in the development of new materials. While the conventional organic synthesis methods can synthesize one kind of compound via a single reaction, the combinatorial chemical synthetic technique is a highly efficient method which can synthesize more various and numerous compounds at the same time or automate the multi-step synthetic process. With the technique, it has become easier to screen a biological hit compound and a lead compound having a new structure, and optimize structure and activity thereof. Combinatorial chemical synthesis has been mainly studied in medicinal chemistry, in particular, contributed to the study of structure-activity relationship, and the skeletal diversity can be ensured via various substitution reactions in a specific structure.
Diversity-oriented synthesis is a new concept in organic synthesis, where the aim is to synthesize collections of structurally-diverse compounds that are broadly distributed in the chemical space, and search for a variety of new biologically active compounds by High Throughput Screening.
In diversity-oriented synthesis, compounds having different core skeletons can be prepared at the same time, and constructed as a library. Thus, a larger number of different active compounds can be identified from the library by various search methods.
If the concept of privileged structure is introduced to the diversity-oriented synthesis, it is very advantageous to search biologically active compounds.
The term “privileged structure” is defined as a single molecular framework contained in many natural products or biologically active molecules. The application of the privileged structure to diversity-oriented synthesis has been attempted over a long period of time. In particular, benzodiazepine is a privileged structure that had been frequently applied to the synthesis by many early chemists, and synthesized by many groups with great interest. The most famous example thereof is a library synthesized by Nicolaou group.
Benzopyran is a privileged structural motif observed in many biologically active natural products, and it plays an important role in binding with various biopolymers. To date, synthesis of bioactive benzopyrans has been extensively studied, especially a combinatorial library based on a privileged benzopyran template has been reported by Nicolaou and coworkers (K. C. Nicolaou and H. J. Mitchell, J. Am. Chem. Soc., 2000, 122, 9939; Y. D. Gong and S. E. Yoo, J. Comb. Chem., 2003, 5, 577; J. Y. Hwang and Y. D. Gong, J. Org. Chem., 2005, 70, 10151; K. C. Nicolaou and J. A. Prefferkorn, Org. Biomol. Chem., 2003, 1, 908; K. Sivakumar and Q. Wang, Org. Let., 2004, 6, 4603; V. A. Ashwood and K. Willcocks, J. Med. Chem., 1986, 29, 2194; R. Bergmann and R. Gericke, J. Med. Chem., 1990, 33, 2759). However, previous reports focused on partial, limited diversifications via substitution for the arene region of benzopyrans by solid phase synthesis.
Natural products and synthetic products having benzopyran skeletons display antioxidant activity. Therefore, benzopyran has been widely known as skeletons for the development of compounds having pharmacological effects such as therapeutic agents for neurological diseases, hypertensions, and diabetes, and extensively utilized.
Accordingly, the present inventors have made extensive studies on compounds having skeletal diversity with a privileged benzopyran substructure through the branching pathway via various chemical transformations such as Diels-Alder reaction, click chemistry, and palladium mediated cross-coupling. Further, they applied diversity-oriented synthesis to the resultants, and synthesized compounds having benzopyran core through the reconstruction of core skeletons in the pyran region, not through the partial, limited modification via substitution for the arene region of benzopyrans. They found that the compounds exhibit excellent cytotoxicity against cancer cells, thereby completing the present invention.